The iron pro-chelator BHAPI attenuates glutamate-induced oxidative stress via Wnt-β/catenin pathway in HT22 cells.

Disturbances in intracellular iron homeostasis are associated with brain damage under various neuropathological conditions. However, exposure of neuronal cells to classical iron chelators could interfere with physiological iron functions in the brain. Thus, iron pro-chelators represent a more advanced approach to exert strong free-iron binding capacity only under oxidative stress conditions. In the present study, we investigated the protective effects of an iron pro-chelator BHAPI [(E)-N'-(1-(2-((4- (4,4,5,5-tetramethyl-1,2,3-dioxoborolan-2-yl)benzyl)oxy)phenyl)ethylidene) isonicotino hydrazide] against glutamate-induced toxicity in neuronal HT22 cells. The results showed that BHAPI significantly increased cell viability, decreased lactate dehydrogenase (LDH) release, inhibited apoptotic cell death and reduced the activation of caspase-3 after glutamate treatment. This protection was accompanied by the preservation of mitochondrial function, as evidenced by reduced mitochondrial oxidative stress, attenuated lipid peroxidation and enhanced ATP generation. In addition, BHAPI promoted Wnt/β-catenin signaling, which was related to destabilization of β-catenin destruction complex. The Wnt/β-catenin signaling inhibitor JW74, but not IWP2, partially prevented the protective effects of BHAPI. In conclusion, our data suggested that BHAPI acted as a neuroprotective agent against glutamate-induced toxicity, and this protection might be mediated by preservation of mitochondrial function and regulation of Wnt/β-catenin pathway.